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Thiazolidinediones Inhibit Growth and Invasiveness of the Human Adrenocortical Cancer Cell Line H295R

Department of Pathophysiology, Endocrinology Unit (P.F., M.S., M.M., G.F.) and Gastroenterology Unit (E.C., M.T., C.G., S.M., A.G.), Center of Research Transfer and Higher Education, University of Florence, 50139 Florence, Italy

Address all correspondence and requests for reprints to: M. Mannelli, M.D., Department of Clinical Pathophysiology, Endocrine Unit, Viale Pieraccini, 6, 50139 Florence, Italy. E-mail: m.mannelli{at}dfc.unifi.it.

Thiazolidinediones (TZDs) are a new class of antidiabetic drugs that have also been shown to possess antitumoral properties in different human cancers. TZDs bind and activate the peroxisome proliferator-activated receptor (PPAR)-, which is a nuclear receptor acting as a transcription factor in several tissues. In the present study, we evaluated PPAR mRNA and protein expression in tissue samples of human adrenocortical carcinomas (ACCs), normal adrenal glands, and the human ACC cell line H295R. PPAR mRNA was expressed in six of eight ACC, two of three normal adrenal glands and the H295R cells. These results were confirmed by immunohistochemistry.

PPAR transcriptional activity in H295R cells, monitored by a reporter gene assay, was induced 2- to 3-fold by TZDs, such as rosiglitazone (RGZ) and pioglitazone, whereas in PPAR-transfected cells RGZ alone or RGZ plus 9-cis retinoic acid further increased reporter activity.

TZDs inhibited both the proliferation and invasiveness of H295R cells in a dose-dependent manner. Thymidine incorporation was reduced by about 60% by 20 µM of both TZDs. Cotreatment with the retinoic X receptor ligand 9-cis retinoic acid had an additive effect.

TZDs increased the number of cells in the G₀/G₁ phase and decreased them in the S phase. Western blot analysis showed that TZDs increased the expression of the cell cycle inhibitors p21 and p27 and reduced the expression of cyclin D1.

Twenty micromoles of RGZ and pioglitazone reduced H295R invasiveness through Matrigel by about 85%.

Zymography and ELISA tests showed that TZD inhibited metalloproteinase-2 secretion by H295R cells in a dose-dependent manner.

These data suggest that TZDs reduce the malignant potential of the H295R ACC cell line and, therefore, might potentially constitute a novel tool in the medical treatment of human ACCs.

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